Institute of Physiology, University of Greifswald, Greifswald, Germany.
J Hypertens. 2018 Apr;36(4):892-903. doi: 10.1097/HJH.0000000000001650.
Antiangiogenic receptor tyrosine kinase inhibitors (RTKI) induce arterial hypertension which may limit their use. Renal fractional sodium excretion (FENa) is reduced in early RTKI-induced hypertension, whereas fractional lithium excretion is unaltered. Therefore, we tested the hypothesis that activated distal tubule and collecting duct sodium reabsorption contributes to RTKI-induced hypertension.
Amiloride-sensitive and hydrochlorothiazide (HCTZ)-sensitive fractional sodium reabsorption (FRNa) and renal epithelial sodium channel (ENaC) as well as sodium chloride cotransporter (NCC) abundances were determined in sunitinib-treated and control rats. The antihypertensive effects of amiloride and HCTZ were investigated by radiotelemery.
After 4 days of treatment, mean arterial pressure was 20 mmHg higher, FENa was lower (0.32 ± 0.08% vs. 0.65 ± 0.14%; P < 0.05), and renal medullary-ENaC protein abundance was higher in sunitinib-treated rats than in controls. Amiloride-sensitive FRNa was 2.37 ± 0.52% in sunitinib-treated rats vs. 2.66 ± 0.44% in controls (n.s.). HCTZ increased FENa by a similar magnitude without affecting amiloride-sensitive FRNa in both groups. After 14 days of treatment, renal medullary β-ENaC protein abundance was higher in rats that received sunitinib than in controls, whereas α-ENaC, γ-ENaC, and NCC abundances were similar in both groups. Amiloride and HCTZ reduced the sunitinib-induced mean arterial pressure rise by 8 ± 3 mmHg (P < 0.05) and 12 ± 2 mmHg (P < 0.05), respectively, without additive effects when combined.
ENaC-dependent and thiazide-sensitive sodium-retaining mechanisms are not overactive in sunitinib-induced hypertension but ENaC blockers and in particular thiazides may be suitable for its treatment.
血管生成受体酪氨酸激酶抑制剂（RTKI）可引起动脉高血压，这可能限制其使用。在 RTKI 诱导的早期高血压中，肾钠排泄分数（FENa）降低，而锂排泄分数不变。因此，我们假设激活的远曲小管和集合管钠重吸收有助于 RTKI 诱导的高血压。
在舒尼替尼治疗和对照组大鼠中，测定阿米洛利敏感和氢氯噻嗪（HCTZ）敏感的钠重吸收分数（FRNa）和肾上皮钠通道（ENaC）以及钠氯共转运体（NCC）的丰度。通过放射性遥测研究阿米洛利和 HCTZ 的降压作用。
治疗 4 天后，平均动脉压升高 20mmHg，FENa 降低（0.32±0.08%对 0.65±0.14%；P<0.05），肾髓质 ENaC 蛋白丰度在舒尼替尼治疗组大鼠高于对照组。舒尼替尼治疗组大鼠的阿米洛利敏感 FRNa 为 2.37±0.52%，对照组为 2.66±0.44%（无统计学差异）。HCTZ 增加 FENa 的幅度相似，而对两组的阿米洛利敏感 FRNa 无影响。治疗 14 天后，舒尼替尼组大鼠肾髓质 β-ENaC 蛋白丰度高于对照组，而 α-ENaC、γ-ENaC 和 NCC 丰度在两组间相似。阿米洛利和 HCTZ 分别降低舒尼替尼诱导的平均动脉压升高 8±3mmHg（P<0.05）和 12±2mmHg（P<0.05），联合使用时无相加作用。
在舒尼替尼诱导的高血压中，ENaC 依赖性和噻嗪类敏感的保钠机制并未过度活跃，但 ENaC 阻滞剂，特别是噻嗪类药物，可能适合其治疗。
